Antiangiogenic hypoxic cytotoxin TX-402 inhibits hypoxia-inducible factor 1 signaling pathway

Anticancer Res. Nov-Dec 2003;23(6a):4427-34.

Abstract

Background: Hypoxia represents an important tumor-specific target for cancer therapy. We have reported that hypoxic cytotoxins, such as TX-1102, tirapazamine (TPZ) and TX-402, selectively induced tumor cells to p53-independent apoptosis under hypoxic conditions and inhibited angiogenesis.

Materials and methods: We investigated the effects of the antiangiogenic hypoxic cytotoxins on hypoxia-induced gene expression and their hypoxia-selective cytotoxicity in human squamous cell carcinoma of the head and neck (SAS cells) and p53-deficient human non-small cell lung carcinoma H1299 cells transfected with either wild-type or mutant p53 gene.

Results: TX-402 had more potent hypoxia-selective cytotoxicity than TPZ in either cell regardless of p53 status. All the compounds inhibited angiogenesis potently at doses of more than 5 micrograms/CAM in chick embryo chorioallantoic membrane (CAM) assay. RT-PCR analyses indicated that TX-402 reduced the inducible expression of vascular endothelial cell growth factors (VEGF) and glucose transporter type 3 (GLUT-3) under hypoxic conditions selectively. The mRNA and protein expression of HIF-1 alpha were also suppressed by TX-402 at the same time.

Conclusion: The potent antiangiogenic effects of hypoxic cytotoxins can be attributed to the suppression of VEGF and HIF-1 induction through the hypoxia-inducible pathway. We show an other aspect of the hypoxic cytotoxin as an HIF-1 inhibitor for hypoxia-targeted therapy to improve cancer treatment and prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Carcinoma, Non-Small-Cell Lung / blood supply
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Cell Hypoxia / genetics
  • Cell Line, Tumor
  • Chick Embryo
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genes, p53
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lung Neoplasms / blood supply
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Nuclear Proteins / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Tirapazamine
  • Transcription Factors*
  • Transfection
  • Triazines / pharmacology*

Substances

  • Angiogenesis Inhibitors
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Transcription Factors
  • Triazines
  • Tirapazamine